Our long-term objective is to attempt to understand the phenomenon of programmed cell death in normal and abnormal growth of the human prostate, namely, benign prostatic hyperplasia and carcinoma of the prostate. In the present study, we will use the rat prostate as an experimental model to study the basic biology of epithelial cell death. Results of our previous studies have indicated the existence of a regional heterogeneity in morphological and functional activities within the ductal system of the rat prostate. Epithelial cells lining the distal regions of the ductal system are active in proliferation and those in the proximal regions are active in proliferation and regression, the location of cell death is reversed, in that, cell death occurs in the distal regions while cells in the proximal regions become viable. Many pieces of evidence have indicated that TGF-beta signaling plays a critical role in epithelial cell death in the rat prostate under both androgen enriched and depleted conditions. We postulate that TGF-beta signaling in the prostatic ductal system is mediated through a local manifestation of stromal-epithelial interaction. As a continuation of our previous efforts, we propose the following specific aims: SPECIFIC AIM 1 (In situ studies): We will continue to study the regional heterogeneity of stromal organization in the prostatic ductal system in both intact and castrated rats. We will conduct morphological studies in an attempt to correlate regional TGF-beta signaling with regional distribution of cytoskeletal proteins during prostatic regression. SPECIFIC AIM 2 (Tissue culture studies): We will establish primary culture systems for prostatic stromal cells. The direct effect of androgen, growth factors (bFGF and TGF-beta), and epithelial cell secretory products will be tested. We will dissect the conditions that regulate the morphological expression of these stromal cells with special reference to TGF-beta expression. SPECIFIC AIM 3 (Transgenic studies): TGF-beta type I and type II contain serine/threonine kinase domains and directly participate in TGF-beta signal transduction. Functional blockade or overexpression of the TGF- beta signaling will provide insights into the mechanism of action of these receptors as well as the cellular mechanism of androgen action. We propose to generate dominant negative mutants to these receptors and to introduce them into prostatic epithelial cells either in culture conditions or in transgenic mouse systems. In addition, we will introduce probasin driven TGF-beta1 in a transgenic system to generate "small prostates."